Aniline-1-indolinone and derivative thereof, and synthetic method and application of aniline-1-indolinone and derivative thereof

Abstract

The invention belongs to the technical field of compound preparation, and particularly relates to aniline-1-indolinone and a derivative thereof as well as a synthesis method and application of the aniline-1-indolinone and the derivative thereof. Through a well-designed synthesis route, the purification and separation steps of the product are greatly simplified, the adopted catalyst is green and environment-friendly, free of metal residues, mild in reaction condition and easy to operate, the global trend of current sustainable development and environmental protection is met, the reaction process is greatly optimized, the potential influence on the environment is reduced, and the method is suitable for industrial production. The aniline-1-indolinone and the derivative thereof disclosed by the invention can be used for preparing anti-tumor drugs, so that a chemical strategy library for synthesizing the anti-tumor drugs is enriched, a new path is opened up for promoting the development of green chemistry in the field of medicines, and extremely wide application prospects and market potentials are shown.

Description

Technical Field

[0001] The present invention belongs to the technical field of compound preparation, and particularly relates to an aniline-1-indolinone and its derivatives, as well as a synthesis method and application thereof. Background Art

[0002] Isoindolinone compounds, as a structural unit commonly present in drug molecules and natural products, have long been a research hotspot in the field of chemical synthesis due to their unique pharmacological activities. These compounds play a crucial role in drug development, and thus the optimization and innovation of their synthesis methods have been highly favored by chemists.

[0003] In recent years, aniline compounds have emerged as important members in the construction of fragment libraries in drug R & D projects. However, despite their increasing applications, there are few dominant reaction types in this field. This is mainly attributed to the application obstacles of amine compounds in the catalytic conversion of Lewis acids, a long-standing problem that limits their extensive utilization in synthetic chemistry and further hinders their incorporation in the process of fragment-based drug discovery. Specifically, amine compounds have poor compatibility with various Lewis acid catalysts and face challenges in terms of chemoselectivity and regioselectivity, which together lead to a decrease in reaction stability.

[0004] In the existing preparation processes of isoindolinone compounds, in order to achieve efficient synthesis, metal catalysts and additives are usually used as auxiliary means. However, this synthesis method can only be carried out under high-temperature conditions, not only with high energy consumption, but also the use of metal catalysts may lead to metal residue problems. This defect severely limits the application scope of the synthesized isoindolinone compounds in the medical field, because metal residues may have adverse effects on the human body, thus affecting the safety and effectiveness of drugs.

[0005] Therefore, aiming at the deficiencies of the existing synthesis methods, the present invention provides a synthesis method of isoindolinone compounds that is efficient, environmentally friendly and applicable to the medical field, providing new ideas and means for drug development and promoting the continuous progress and development of the pharmaceutical industry. Summary of the Invention

[0006] Aiming at the above problems, the purpose of the present invention is to provide an aniline-1-indolinone and its derivatives, as well as a synthesis method and application thereof.

[0007] The technical content of the present invention is as follows:

[0008] The present invention provides an aniline-1-indolinone and its derivatives, and their chemical structures are as follows:

[0009]

[0010] Among them, R 1 is an aliphatic hydrocarbon group or an aromatic hydrocarbon group;

[0011] R 2 is hydrogen, an alkyl group, an alkoxy group, a hydroxyl group, a cyano group, an amino group, a nitro group, a halogen group or a phenyl group;

[0012] R 3 and R 4 are an alkyl group, an aryl group or a substituted phenyl group.

[0013] The present invention also provides a method for synthesizing aniline-1-indolinone and its derivatives, comprising the following steps:

[0014] At room temperature, an isatin compound and an aniline compound are added to an organic solvent and reacted under the catalysis of binaphthyl phosphate. After the reaction is completed, purification is carried out to obtain a series of aniline-1-indolinone and its derivatives. The chemical reaction process is as follows:

[0015]

[0016] The molar ratio of the isatin compound to the aniline compound is 1:1.2;

[0017] The organic solvent includes dichloromethane DCM;

[0018] The addition amount of the binaphthyl phosphate is 5-8 mol%;

[0019] The preparation of the isatin compound comprises the following steps: Dissolve the phthalimide compound in an organic solvent, cool to 0 °C, slowly add the corresponding Grignard reagent, stir and react at 0 °C, then quench the reaction, carry out extraction, and dry the obtained organic layer over anhydrous sodium sulfate, filter, and purify to obtain a series of isatin compounds;

[0020] The corresponding Grignard reagent refers to the Grignard reagent with R 1 substituents, that is Among them, the Grignard reagent is 1.0 M in THF.

[0021] The usage equivalent ratio of the phthalimide compound to the Grignard reagent is 1:(3-5);

[0022] The chemical structure of the isatin compound is as follows:

[0023]

[0024] Among them, R 1 is an aliphatic hydrocarbon group or an aromatic hydrocarbon group, R 2is hydrogen, alkyl, alkoxy, hydroxyl, cyano, amino, nitro, halogen or phenyl;

[0025] The aniline compounds include N-substituted aniline compounds, and their chemical structure is where R 3 and R 4 are alkyl, aryl or substituted phenyl, including: diphenylamine, p-methyl diphenylamine, 3-methyl diphenylamine, N-benzylaniline, triphenylamine, N,N-dimethylaniline, 3,4-dimethyl diphenylamine, 4-methyl triphenylamine, N-methyl diphenylamine, 4-fluoro diphenylamine, 4-methoxy-N-phenylaniline, 4-bromo phenylaniline and N-methylaniline, etc.

[0026] The present invention also provides an application of aniline-1-indolinone and its derivatives in the preparation of anti-tumor drugs;

[0027] The tumors include liver cancer, breast cancer, virus infection, etc.

[0028] The beneficial effects of the present invention are as follows:

[0029] The synthesis method of aniline-1-indolinone and its derivatives of the present invention uses a catalyst that is not only green and environmentally friendly, without metal residues, but also has mild reaction conditions and is easy to operate, meeting the current global trend of sustainable development and environmental protection. Moreover, it greatly optimizes the reaction process and reduces the potential impact on the environment. Compared with the traditional synthesis route, this method significantly improves the reaction conditions to make them more mild, thereby reducing energy consumption and potential safety risks. In terms of operation, the process is simplified and intuitive, reducing cumbersome steps and complex technical requirements, making the synthesis process easier to control and implement. Particularly importantly, through the carefully designed synthesis route, the purification and separation steps of the product are greatly simplified, not only improving work efficiency, but also ensuring high purity and high yield of the final product, laying a solid foundation for the production of such anti-tumor drugs. In summary, the proposed invention not only enriches the chemical strategy library for the synthesis of anti-tumor drugs, but also opens up a new path for promoting the development of green chemistry in the pharmaceutical field, showing extremely broad application prospects and market potential. Specific Embodiments

[0030] The following further describes the present invention in detail through specific implementation cases. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the protection scope of the present invention. After reading the present invention, various equivalent modifications made by those skilled in the art fall within the scope defined by the appended claims of this application.

[0031] Unless otherwise specified, all raw materials and reagents of the present invention are raw materials and reagents in the conventional market.

[0032] The corresponding Grignard reagent in the present invention refers to a Grignard reagent with R 1 substituent, that is Among them, the Grignard reagent is commercially available and is 1.0 M in THF.

[0033] Example 1

[0034] A method for synthesizing aniline-1-indolinone and its derivatives

[0035] 1) Preparation of phenyl-substituted isoindolinone:

[0036] Take 5 mmol of phthalimide in a reaction flask, add 15 mL of dry THF to dissolve it, cool it to 0 °C, and then slowly add 15 mmol of phenylmagnesium bromide with a syringe. The reaction is tracked by spotting on a thin-layer chromatography plate until the raw materials are completely reacted. After the reaction is completed, add saturated ammonium chloride solution to quench the reaction, then extract the reaction solution with 30 mL of ethyl acetate, wash the reaction solution with 30 mL of saturated sodium carbonate, add anhydrous sodium sulfate to dry the reaction solution after washing, and let it stand for 5 min. Finally, concentrate the reaction solution, and then use a silica gel column for separation and purification. The purified product is rotary evaporated to obtain phenyl-substituted isoindolinone. The reaction formula is as follows:

[0037]

[0038] 2) Preparation of aniline-1-indolinone and its derivatives

[0039] Take 0.1 mmol of phenyl-substituted isoindolinone and 0.12 mmol of p-methyl diphenylamine in a reaction flask, add 1.8 mg of binaphthyl phosphate, then add 2 mL of dichloromethane to dissolve, continuously stir at room temperature, and track the reaction by spotting on a thin-layer chromatography plate until the raw materials are completely reacted. After the reaction is completed, use a silica gel column for separation and purification. The purified product is rotary evaporated to obtain the target product, and the NMR analysis is as follows: 1 H NMR(400MHz,CDCl3)δ7.78(d,J=7.5Hz,1H),7.46(t,J=7.4Hz,1H),7.37(dd,J=15.0,7.5Hz,2H),7.28–7.18(m,5H),7.05–6.95(m,5H),6.90(d,J=8.3Hz,2H),6.81(d,J=8.6Hz,2H),5.62(s,1H),2.21(s,3H). 1313C NMR (101 MHz, CDCl3) δ 169.90, 150.63, 143.93, 142.99, 139.60, 133.74, 132.24, 131.53, 130.64, 129.90, 128.57, 128.33, 128.24, 127.84, 127.08, 124.44, 124.23, 119.49, 116.07, 70.71, 20.69. The yield was 99%. The reaction formula is as follows:

[0040]

[0041] The structure of the binaphthol phosphate is

[0042] Example 2

[0043] A method for synthesizing aniline-1-indolinone and its derivatives

[0044] Take 0.1 mmol of phenyl-substituted isoindolinone and 0.12 mmol of N-methylaniline in a reaction flask, add 1.8 mg of binaphthol phosphate, then add 2 mL of dichloromethane to dissolve, stir continuously at room temperature, and monitor the reaction by spotting on a thin-layer chromatography plate until the raw materials are completely reacted. After the reaction is completed, separate and purify using a silica gel column, and rotary evaporate the purified product to obtain the target product. NMR analysis: 1 1H NMR (400 MHz, CDCl3) δ 7.83 (dd, J = 16.1, 5.8 Hz, 1H), 7.53 (td, J = 7.5, 1.0 Hz, 1H), 7.43 (dd, J = 17.7, 7.6 Hz, 2H), 7.37–7.24 (m, 6H), 7.03 (d, J = 8.7 Hz, 2H), 6.94 (s, 1H), 6.52 (d, J = 8.6 Hz, 2H), 2.80 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 169.89, 150.86, 148.73, 143.20, 132.21, 130.99, 130.58, 128.63, 128.51, 128.23, 127.76, 127.07, 124.42, 124.17, 112.34, 70.74, 29.71. The yield was 99%. The reaction formula is as follows:

[0045]

[0046] Example 3

[0047] A method for synthesizing aniline-1-indolinone and its derivatives

[0048] 1) Preparation of isoindolinone:

[0049] Take 5 mmol of 4,5-dichlorophthalimide in a reaction flask, add 15 mL of dry THF to dissolve it, cool to 0 °C, and slowly add 15 mmol of phenylmagnesium bromide with a syringe. Track the reaction by spotting on a thin-layer chromatography plate until the raw materials are completely reacted. After the reaction is completed, quench the reaction with saturated ammonium chloride solution, then extract the reaction solution with 30 mL of ethyl acetate, wash the reaction solution with 30 mL of saturated sodium carbonate, and after the washing is completed, add anhydrous sodium sulfate to dry the reaction solution and let it stand for 5 min. Finally, concentrate the reaction solution and then separate and purify it using a silica gel column. The purified product is rotary evaporated to obtain 4,5-dichlorophenyl-substituted isoindolinone. The reaction formula is as follows:

[0050]

[0051] 2) Take 0.1 mmol of 4,5-dichlorophenyl-substituted isoindolinone and 0.12 mmol of p-methyl diphenylamine in a reaction flask, add 1.8 mg of binaphthyl phosphate, then add 2 mL of dichloromethane to dissolve, stir continuously at room temperature, and track the reaction by spotting on a thin-layer chromatography plate until the raw materials are completely reacted. After the reaction is completed, separate and purify it using a silica gel column. The purified product is rotary evaporated to obtain the target product. NMR analysis: 1 H NMR(400MHz,DMSO)δ9.89(s,1H),8.12(s,1H),7.97(s,1H),7.91(s,1H),7.41–7.27(m,5H),7.11–7.02(m,4H),7.01–6.92(m,4H),2.22(s,3H). 13 CNMR(101MHz,DMSO)δ166.50,150.75,144.28,143.00,140.63,135.44,132.38,132.33,132.16,130.06,129.66,128.95,128.42,128.18,127.43,127.31,125.55,118.43,115.72,70.19,20.76. The yield is 67%. The reaction formula is as follows:

[0052]

[0053] Example 4

[0054] A synthetic method of aniline-1-isoindolinone and its derivatives

[0055] 1) Preparation of 4-fluorophenyl-substituted isoindolinone:

[0056] Take 5 mmol of phthalimide in a reaction flask, add 15 mL of dry THF to dissolve it, cool to 0 °C, and slowly add 15 mmol of 4-fluorophenylmagnesium bromide with a syringe. Track the reaction by spotting on a thin-layer chromatography plate until the raw materials are completely reacted. After the reaction is completed, add saturated ammonium chloride solution to quench the reaction, then extract the reaction solution with 30 mL of ethyl acetate, wash the reaction solution with 30 mL of saturated sodium carbonate, and after washing, add anhydrous sodium sulfate to dry the reaction solution and let it stand for 5 min. Finally, concentrate the reaction solution and then use a silica gel column for separation and purification. Rotate evaporate the purified product to obtain 4-fluorophenyl-substituted isoindolinone. The reaction formula is as follows:

[0057]

[0058] 2) Take 0.1 mmol of 4-fluorophenyl-substituted isoindolinone and 0.12 mmol of p-methyl diphenylamine in a reaction flask, add 1.8 mg of binaphthol phosphate, then add 2 mL of dichloromethane to dissolve, stir continuously at room temperature, and track the reaction by spotting on a thin-layer chromatography plate until the raw materials are completely reacted. After the reaction is completed, use a silica gel column for separation and purification. Rotate evaporate the purified product to obtain the target product, NMR analysis: 1 H NMR(400MHz,DMSO)δ9.67(s,1H),8.10(s,1H),7.73(d,J=7.5Hz,1H),7.65–7.58(m,2H),7.55–7.48(m,1H),7.39–7.30(m,2H),7.17(t,J=8.9Hz,2H),7.06(dd,J=14.3,8.6Hz,4H),7.01–6.94(m,4H),2.21(s,3H). 19 F NMR(376MHz,DMSO)δ-115.35(s). 13 C NMR(101MHz,DMSO)δ168.79,163.04,160.62,150.70,144.06,140.73,140.32,140.29,133.39,132.49,131.51,130.05,129.56,129.52,129.44,128.83,128.29,125.12,123.74,118.31,115.78,115.62,115.40,69.84,20.76. The yield is 95%. The reaction formula is as follows:

[0059]

[0060] Example 5

[0061] A synthesis method of aniline-1-isoindolinone and its derivatives

[0062] Take 0.1 mmol of phenyl-substituted isoindolinone and 0.12 mmol of 4-methoxy-N-phenylaniline in a reaction flask, add 1.8 mg of binaphthol phosphate, then add 2 mL of dichloromethane to dissolve, stir continuously at room temperature, and track the reaction by spotting on a thin-layer chromatography plate until the raw materials are completely reacted. After the reaction is completed, separate and purify using a silica gel column, rotary evaporate the purified product to obtain the target product, and perform NMR analysis: 1 H NMR(400MHz,DMSO)δ9.61(s,1H),7.92(s,1H),7.71(d,J=7.5Hz,1H),7.60(d,J=2.6Hz,2H),7.50(ddd,J=8.1,6.5,4.0Hz,1H),7.34–7.26(m,5H),7.03(dd,J=8.8,1.9Hz,4H),6.88–6.83(m,4H),3.70(s,3H). 13 C NMR(101MHz,DMSO)δ168.82,154.44,150.83,145.00,144.16,136.25,132.88,132.35,131.61,128.71,128.41,128.30,127.81,127.36,125.20,123.66,121.14,121.05,114.99,114.71,70.30,55.68. The yield is 99%. The reaction formula is as follows:

[0063]

[0064] Example 6

[0065] A method for synthesizing aniline-1-isoindolinone and its derivatives

[0066] Take 0.1 mmol of phenyl-substituted isoindolinone and 0.12 mmol of N-methyldiphenylamine in a reaction flask, add 1.8 mg of binaphthol phosphate, then add 2 mL of dichloromethane to dissolve, stir continuously at room temperature, and track the reaction by spotting on a thin-layer chromatography plate until the raw materials are completely reacted. After the reaction is completed, separate and purify using a silica gel column, rotary evaporate the purified product to obtain the target product, and perform NMR analysis: 1 H NMR(400MHz,CDCl3)δ7.86(d,J=7.5Hz,1H),7.54(td,J=7.5,1.1Hz,1H),7.48–7.41(m,2H),7.37–7.28(m,5H),7.27–7.23(m,2H),7.13–6.95(m,6H),6.83(d,J=8.8Hz,2H),3.27(s,3H).13 13C NMR (101 MHz, CDCl3) δ 169.99, 150.62, 148.60, 148.46, 143.00, 133.71, 132.21, 129.38, 128.57, 128.33, 127.99, 127.83, 127.10, 124.48, 124.23, 122.80, 122.57, 117.99, 70.74, 40.16. The yield was 75%. The reaction formula is as follows:

[0067]

[0068] Example 7

[0069] Synthesis method of aniline-1-indolinone and its derivatives

[0070] 1) Preparation of 4-methoxyphenyl-substituted isoindolinone:

[0071] Take 5 mmol of phthalimide in a reaction flask, add 15 mL of dry THF to dissolve it, cool to 0 °C, and then slowly add 15 mmol of 4-methoxyphenylmagnesium bromide with a syringe. Track the reaction by spotting on a thin-layer chromatography plate until the raw materials are completely reacted. After the reaction is completed, quench the reaction with saturated ammonium chloride solution, then extract the reaction solution with 30 mL of ethyl acetate, wash the reaction solution with 30 mL of saturated sodium carbonate, after washing, add anhydrous sodium sulfate to dry the reaction solution, and let it stand for 5 min. Finally, concentrate the reaction solution and then use a silica gel column for separation and purification. The purified product is rotary evaporated to obtain 4-methoxyphenyl-substituted isoindolinone. The reaction formula is as follows:

[0072]

[0073] 2) Preparation of aniline-1-indolinone and its derivatives

[0074] Take 0.1 mmol of 4-methoxyphenyl-substituted isoindolinone and 0.12 mmol of p-methyl diphenylamine in a reaction flask, add 1.8 mg of binaphthyl phosphate, then add 2 mL of dichloromethane to dissolve, stir continuously at room temperature, and track the reaction by spotting on a thin-layer chromatography plate until the raw materials are completely reacted. After the reaction is completed, use a silica gel column for separation and purification. The purified product is rotary evaporated to obtain the target product, NMR analysis: 11H NMR (400 MHz, DMSO) δ 9.56 (s, 1H), 8.06 (s, 1H), 7.69 (d, J = 7.4 Hz, 1H), 7.63–7.54 (m, 2H), 7.49 (t, J = 7.0 Hz, 1H), 7.20 (d, J = 8.7 Hz, 2H), 7.05 (dd, J = 13.8, 8.5 Hz, 4H), 6.96 (t, J = 8.3 Hz, 4H), 6.89 (d, J = 8.8 Hz, 2H), 3.35 (s, 6H). 13 13C NMR (101 MHz, DMSO) δ 168.76, 158.91, 151.17, 143.87, 140.83, 135.95, 133.87, 132.32, 131.55, 130.04, 129.44, 128.63, 128.29, 125.09, 123.62, 118.21, 115.79, 114.08, 69.89, 55.58, 20.74. The yield was 67%. The reaction formula is as follows:

[0075]

[0076] Example 8

[0077] A method for synthesizing aniline-1-indolinone and its derivatives

[0078] 1) Preparation of m-tolyl-substituted isoindolinone:

[0079] Take 5 mmol of phthalimide in a reaction flask, add 15 mL of dry THF to dissolve it, cool to 0 °C, and slowly add 15 mmol of m-tolylmagnesium bromide with a syringe. Track the reaction by spotting on a thin-layer chromatography plate until the raw materials are completely reacted. After the reaction is completed, quench the reaction with saturated ammonium chloride solution, then extract the reaction solution with 30 mL of ethyl acetate, wash the reaction solution with 30 mL of saturated sodium carbonate, and after the washing is completed, add anhydrous sodium sulfate to dry the reaction solution and let it stand for 5 min. Finally, concentrate the reaction solution and then use a silica gel column for separation and purification. Rotavaporize the purified product to obtain m-tolyl-substituted isoindolinone. The reaction formula is as follows:

[0080]

[0081] 2) Preparation of aniline-1-indolinone and its derivatives

[0082] Take 0.1 mmol of m - methylphenyl - substituted isoindolinone and 0.12 mmol of p - methyl diphenylamine in a reaction flask, add 1.8 mg of binaphthyl phosphate, then add 2 mL of dichloromethane to dissolve. Stir continuously at room temperature, and monitor the reaction by spotting on a thin - layer chromatography plate until the raw materials are completely reacted. After the reaction is completed, perform separation and purification using a silica gel column. Rotavaporize the purified product to obtain the target product. NMR analysis: 1 H NMR(400MHz,DMSO)δ9.59(s,1H),8.08(s,1H),7.70(d,J=7.4Hz,1H),7.60(t,J=5.8Hz,2H),7.55–

[0083] 7.44(m,1H),7.21(t,J=7.6Hz,1H),7.14(s,1H),7.11–7.01(m,6H),6.96(t,J=8.7Hz,4H),2.25(s,3H),2.21(s,3H). 13 C NMR(101MHz,DMSO)δ168.82,150.78,144.05,143.91,140.78,137.86,133.70,132.34,131.60,130.05,129.48,128.69,128.49,128.35,127.75,125.23,124.61,123.66,118.26,115.74,70.28,21.66,20.77. The yield is 90%. The reaction formula is as follows:

[0084]

[0085] Example 9

[0086] A method for synthesizing aniline - 1 - isoindolinone and its derivatives

[0087] 1) Preparation of m - tolyl - substituted isoindolinone:

[0088] Take 5 mmol of phthalimide in a reaction flask, add 15 mL of dry THF to dissolve, cool to 0 °C, and then slowly add 15 mmol of 4 - chlorophenylmagnesium bromide with a syringe. Monitor the reaction by spotting on a thin - layer chromatography plate until the raw materials are completely reacted. After the reaction is completed, add saturated ammonium chloride solution to quench the reaction, then extract the reaction solution with 30 mL of ethyl acetate, wash the reaction solution with 30 mL of saturated sodium carbonate, after washing, add anhydrous sodium sulfate to dry the reaction solution, and let it stand for 5 min. Finally, concentrate the reaction solution, and perform separation and purification using a silica gel column. Rotavaporize the purified product to obtain 4 - chlorophenyl - substituted isoindolinone. The reaction formula is as follows:

[0089]

[0090] 2) Preparation of Aniline-1-indolinone and Its Derivatives

[0091] Take 0.1 mmol of 4-chlorophenyl-substituted isoindolinone and 0.12 mmol of p-methyl diphenylamine in a reaction flask, add 1.8 mg of binaphthol phosphate, then add 2 mL of dichloromethane to dissolve. Stir continuously at room temperature and track the reaction by spotting on a thin-layer chromatography plate until the raw materials are completely reacted. After the reaction is completed, use a silica gel column for separation and purification. Rotavaporize the purified product to obtain the target product. NMR analysis: 1 H NMR(400MHz,DMSO)δ9.66(s,1H),8.10(s,1H),7.71(d,J=7.5Hz,1H),7.65–7.58(m,2H),7.56–7.49(m,1H),7.40(d,J=8.6Hz,2H),7.31(d,J=8.6Hz,2H),7.05(dd,J=8.3,6.6Hz,4H),6.96(dd,J=8.4,6.4Hz,4H),2.21(s,3H). 13 C NMR(101MHz,DMSO)δ168.76,150.39,144.11,143.17,140.70,133.07,132.61,132.55,131.51,130.10,130.05,129.99,129.58,129.30,129.27,128.93,128.76,128.34,128.30,125.12,123.77,118.40,118.35,115.78,115.71,69.85,20.79. The yield is 96%. The reaction formula is as follows:

[0092]

[0093] Example 10

[0094] A Synthesis Method of Aniline-1-indolinone and Its Derivatives

[0095] Take 0.1 mmol of phenyl-substituted isoindolinone and 0.12 mmol of 4-bromophenyl aniline in a reaction flask, add 1.8 mg of binaphthol phosphate, then add 2 mL of dichloromethane to dissolve. Stir continuously at room temperature and track the reaction by spotting on a thin-layer chromatography plate until the raw materials are completely reacted. After the reaction is completed, use a silica gel column for separation and purification. Rotavaporize the purified product to obtain the target product. NMR analysis: 11H NMR (400 MHz, DMSO) δ 9.66 (s, 1H), 8.38 (s, 1H), 7.72 (d, J = 7.5 Hz, 1H), 7.62 (d, J = 3.8 Hz, 2H), 7.55–7.48 (m, 1H), 7.32 (ddd, J = 10.5, 7.0, 5.4 Hz, 7H), 7.13 (d, J = 8.7 Hz, 2H), 7.02 (dd, J = 10.3, 8.9 Hz, 4H). 13 13C NMR (101 MHz, DMSO) δ 168.83, 150.63, 143.94, 143.13, 142.57, 135.11, 132.43, 132.27, 131.60, 128.81, 128.45, 127.89, 127.36, 125.22, 123.71, 118.84, 117.27, 110.86, 70.29. The yield was 81%. The reaction formula is as follows:

[0096]

[0097] Select the products of Examples 1, 2, 4, 6, 7, 8, 9, and 10 above for anti-tumor testing:

[0098] Dissolve the aniline-1-indolinone compound to be tested in DMSO and dilute it with complete medium respectively, so that the final concentration of the drug for primary screening is 100 μM, the final concentration of the drug for secondary screening is 20 μM, and ensure that the final concentration of DMSO in the 96-well plate does not exceed 5‰.

[0099] Respectively take 100 μL of single-cell suspension of hepatocellular carcinoma cells SK-Hep1 or breast cancer cells MCF-7 in the logarithmic growth phase with a concentration of 5 - 10×10 4 cells / mL and inoculate them into each well of a 96-well plate (only add PBS buffer to the outermost circle of the 96-well plate, which is not used for cell experiments and is used to prevent errors in drug concentration caused by water evaporation in the inner circle), and culture them overnight in an incubator at 37°C with 5% carbon dioxide. Then add 1 μL of the drug to the cell suspension in each well. Set 4 replicates for each drug concentration. Paclitaxel is used as a positive control drug, and a blank control group (only add medium) and a negative control group are set. After 48 hours of continuous cell culture, add 100 μL of serum-free culture solution of MTT (concentration is 5 mg / mL) to each well, and continue to incubate for 4 h. Carefully discard the supernatant, add 100 μL of DMSO solution to each well, shake to fully dissolve the crystals, and measure the OD value at 490 nm with an enzyme-linked immunosorbent assay (ELISA) reader. Calculate the inhibition rate according to the following formula, and use SPSS software to calculate the corresponding IC 50 value.

[0100] Inhibition rate % = [1 - (OD experimental group / OD control group)] × 100%.

[0101] The results are as follows:

[0102] Table 1 Primary screening of anti-tumor activity (inhibition rate at 20 μM)

[0103]

[0104]

[0105] Table 2 Anti-tumor IC 50 value

[0106] Compound Sk-Hep-1 MCF-7 Example 1 15.55±0.5 14.77±1.7

[0107] As can be seen from Table 1 and Table 2, Example 1 showed the strongest anti-tumor activity among all the tested compounds, had significant inhibitory effects on both liver cancer and breast cancer, and had a relatively low IC50 value, indicating potential clinical application value; Example 2 had a certain inhibitory effect on liver cancer, but the effect on breast cancer was not clear and further research was needed; Examples 4, 6, 7, 8, and 10 mainly showed inhibitory effects on liver cancer, while the inhibitory effects on breast cancer were weak or not clear. Example 9 had moderate inhibitory effects on both liver cancer and breast cancer. In summary, a series of aniline-1-indolinone and its derivatives synthesized in the present invention have obvious anti-tumor effects.

Claims

1. An aniline-1-indolinone and its derivatives, characterized in that, Its chemical structure is as follows: wherein, R 1 is an aliphatic hydrocarbon group or an aromatic hydrocarbon group; R 2 is hydrogen, alkyl, alkoxy, hydroxy, cyano, amino, nitro, halo or phenyl; R 3 and R 4 is an alkyl group, an aryl group or a substituted phenyl group.

2. A method for synthesizing the aniline-1-indolinone and its derivatives according to claim 1, characterized in that, It includes the following steps: At room temperature, an isoindolinone compound and an aniline compound are added to an organic solvent and reacted under the catalysis of binaphthyl phosphate. After the reaction is completed, purification is carried out to obtain a series of aniline-1-isoindolinone and its derivatives. The chemical reaction process is as follows:

3. The synthesis method of aniline-1-indolinone and its derivatives according to claim 2, characterized in that, The molar ratio of the isoindolinone compound to the aniline compound is 1:1.

2.

4. The synthesis method of aniline-1-indolinone and its derivatives according to claim 2, characterized in that, The organic solvent includes dichloromethane (DCM).

5. The synthesis method of aniline-1-indolinone and its derivatives according to claim 2, characterized in that, The addition amount of the binaphthyl phosphate is 5-8 mol%.

6. The synthesis method of aniline-1-indolinone and its derivatives according to claim 2, characterized in that, The preparation of the isoindolinone compound includes the following steps: Dissolve the phthalimide compound in an organic solvent, cool it to 0 °C, slowly add the corresponding Grignard reagent, stir and react at 0 °C, then quench the reaction, carry out extraction, and the obtained organic layer is dried over anhydrous sodium sulfate, filtered, and purified to obtain a series of isoindolinone compounds; The corresponding Grignard reagent refers to a Grignard reagent with an R 1 substituent, that is wherein, the Grignard reagent is 1.0 M in THF.

7. The synthesis method of aniline-1-indolinone and its derivatives according to claim 2, characterized in that, The usage equivalent ratio of the phthalimide compound to the Grignard reagent is 1:(3-5).

8. The synthesis method of aniline-1-indolinone and its derivatives according to claim 2, characterized in that, The chemical structure of the isoindolinone compound is as follows: Among them, R 1 is an aliphatic hydrocarbon group or an aromatic hydrocarbon group, and R2 is hydrogen, an alkyl group, an alkoxy group, a hydroxyl group, a cyano group, an amino group, a nitro group, a halogen group or a phenyl group.

9. The synthesis method of aniline-1-indolinone and its derivatives according to claim 2, characterized in that, The aniline compounds include N-substituted aniline compounds, and their chemical structure is wherein R 3 and R 4 are alkyl, aryl or substituted phenyl, including: Diphenylamine, p-methyl diphenylamine, 3-methyl diphenylamine, N-benzylaniline, triphenylamine, N,N-dimethylaniline, 3,4-dimethyl diphenylamine, 4-methyl triphenylamine, N-methyl diphenylamine, 4-fluorodiphenylamine, 4-methoxy-N-phenylaniline, 4-bromophenylaniline, and N-methylaniline, etc.

10. Use of the aniline-1-isoindolinone and its derivatives according to claim 1 in the preparation of anti-tumor drugs.

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